A high molecular weight synthetic basic random copolymer consisting of L-Alanine (L-Ala), L-Glutamic acid (L-Glu), L-Lysine (L-Lys) and L-Tyrosine (L-Tyr) residues in a molar ratio of about 6 parts L-Ala to 2 parts L-Glu to 4.5 parts L-Lys to 1 part L-Tyr, and having a molecular weight of 15,000-25,000, was first described in U.S. Pat. No. 3,849,550 as an agent for the treatment or prevention of experimental allergic encephalomyelitis (EAE), a disease resembling multiple sclerosis (MS) that can be induced in susceptible animals. Batches of this copolymer of average molecular weight 23,000 Daltons (Da), designated “Copolymer” 1 or “Cop” 1, were shown to be highly effective in protecting and suppressing EAE in several animal species (Teitelbaum et al. 1971, Eur. J. Immunol. 1(4), 242-248; Teitelbaum et al. 1974, Clin. Immunol. Immunopathol. 3(2), 256-262; Teitelbaum et al. 1974, Israel J. Med. Sci. 13:1038).
Later, Copolymer 1 was found to significantly reduce the number of relapses in patients with the exacerbating-remitting form of multiple sclerosis (Bornstein et al. 1990, Handbook of Multiple Sclerosis, ed. Cook S. D. Marcel Dekker, Inc., p. 469; Sela et al. 1990, Bull. Inst. Pasteur (Paris) 88, 303-314; Johnson et al. 1994, MS. 11th Annual Meeting A.N.A.). Copolymer 1, in the form of the acetate salts of synthetic polypeptides containing L-Glu, L-Ala, L-Tyr and L-Lys with an average molar fraction of 0.141, 0.427, 0.095 and 0.338, respectively, is the active ingredient of COPAXONE®, a medicament for the treatment of multiple sclerosis. COPAXONE® is the registered trade name for glatiramer acetate. Chemically, glatiramer acetate or Copolymer 1 is designated L-Glu polymer with L-Ala, L-Lys, and L-Tyr, acetate salt, and its structural formula is:(Glu,Ala,Lys,Tyr)x.xCH3COOH(C5H9NO4.C3H7NO2.C6H14N2O2.C9H11NO3)x.xC2H4O2 
The effect of Copolymer 1 in the treatment of multiple sclerosis is in the achievement of suppression or deactivation of autoimmune T cell reactivity to myelin antigens in multiple sclerosis patients. For this purpose, Copolymer 1 is administered without adjuvants by daily subcutaneous injection.
Copolymer 1 was originally designed to mimic myelin basic protein (MBP) and to induce EAE, but was found to be non-encephalitogenic and to even suppress EAE induced by MBP (Teitelbaum et al. 1971, Eur. J. Immunol. 1(4), 242-248), proteolipid protein (PLP) (Teitelbaum et al. 1996, J. Neuroimmunol. 64, 209-217), or oligodendrocyte glycoprotein (MOG) (Ben-Nun et al. 1996, J. Neurol. 243(4Sup1), S14-22). The precise mechanisms by which Copolymer 1 prevents the development of EAE and ameliorates multiple sclerosis (MS) are not yet known. Nevertheless, some important immunological properties of this copolymer have emerged. Studies have demonstrated partial cross-reactivity of Copolymer 1 with MBP at both the T cell (Webb et al. 1973, Immunol. Commun. 2(2), 185-192) and the antibody (Teitelbaum et al. 1988, Proc. Natl. Acad. Sci. USA 85(24), 9724-9728) level. Copolymer 1 can serve as an antagonist of the T-cell antigen receptor for the MBP immunodominant epitope (Aharoni et al. 1988, J. Neuroimmunol. 91(1-2), 135-146). It can also bind to various MHC class II molecules and prevent them from binding to T cells with specific antigen-recognition properties (Fridkis-Hareli et al. 1999, Int. Immunol. 11(5), 635-641).
Currently COPAXONE® is approved for reduction of the frequency of relapses in patients with Relapsing-Remitting Multiple Sclerosis (RRMS). The composition, its manner of manufacture and methods of treatment using same are described in U.S. Pat. Nos. 5,981,589; 6,054,430; 6,342,476; 6,362,161; 6,620,847; 6,939,539. Further extensive uses of Copolymer 1 and related peptides and polypeptides as well as T cells treated therewith for neuroprotective therapy is disclosed in numerous publications and patents including WO 01/93893, U.S. Pat. Nos. 6,835,711 and 6,844,314, among others.
Recently it was found that in animal models, Copolymer 1 provides beneficial effects in several additional disorders. Thus, Copolymer 1 suppresses the immune rejection manifested in graft versus host disease (GVHD) in case of bone marrow transplantation (U.S. Pat. No. 5,858,964), as well as in graft rejection in case of solid organ transplantation (WO 00/27417).
WO 01/52878 and WO 01/93893 disclose that Copolymer 1 and related peptides and polypeptides as well as T cells activated by these peptides and polypeptides protect central nervous system (CNS) cells from glutamate toxicity and prevent or inhibit neuronal degeneration or promote nerve regeneration in the CNS and peripheral nervous system (PNS). Copolymer 1 has also been proposed as a treatment for neurodegenerative diseases such as optic neuropathies and glaucoma. WO 08/075,365 discloses the use of random or ordered copolymers including Copolymer 1 for treating, preventing, delaying or diminishing age-related deterioration of retinal function.
Copolymer 1 and related copolymers and peptides have been disclosed for treating autoimmune diseases other than multiple sclerosis in WO 00/05250. WO 00/27417 discloses compositions and methods for treating and preventing host-versus-graft immune responses and graft-versus-host diseases comprising as an active ingredient Copolymer 1 and Copolymer 1-related random heteropolymers.
There is an unmet medical need for new compositions for the treatment of autoimmune diseases and, in particular, multiple sclerosis, with desired pharmacological profile and few side effects.